JPH10182647A - Khellactone derivative and platelet aggregation inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound capable of exhibiting excellent platelet activation factor(PAF) antagonist activity and useful as an active compound of a platelet aggregation inhibitor. SOLUTION: This is a khellactone derivative expressed by formula I [R<1> is a 1-22C aliphatic hydrocarbon; either of R<2> or R<3> is H and the other is a group of formula II (either of R<6> or R<7> is H and the other is methyl); either of R<4> or R<5> is H and the other is a group of formula III (either of R<8> or R<9> is H and the other is methyl)] and (±)-cis-3-methoxy-3',4'-ditigloylkhellactone is exemplified. The compound of the formula I is obtained by, e.g. acetylating 2,4-dihydroxybenzaldehyde as a starting raw material with acetic anhydride, introducing to a coumarin skeleton by cyclocondensing with N-acetylglycine, further introducing to a seselin skeleton and acylating. The derivative is expected as a preventive or a curing agent for asthma, arthritis or glomerular nephritis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel silactone derivative and a drug containing the silactone derivative as an active ingredient, which is an inhibitor of platelet aggregation that acts as a platelet activating factor antagonist.

[0002]

2. Description of the Related Art Platelet activating factor (hereinafter abbreviated as PAF)
(J. Exp. Med., 136, 1356-137)
5,1972) is an alkyl lysophospholipid having a long-chain alkyl group at the 1-position of the glycerol skeleton through an ether bond and an acetyl group at the 2-position (J. Biol. Che).
m. , 255, 5514-5516, 1980), and are produced by various cells such as neutrophils, basophils, monocytes, and vascular endothelial cells in response to stimulation. PAF activates various cells including platelets by being recognized in vivo by a PAF receptor on the surface of a target cell. PAF
The receptor is human leukocytes (J. Biol. Chem., 26
6, 20400-20405, 1991) and guinea pig lung (Nature, 349, 342-346, 19).
91) have been identified, and it has been clarified that each is a seven-transmembrane G protein-coupled receptor consisting of 342 amino acid units.

[0003] As physiological functions of PAF, platelet activation, smooth muscle contraction of bronchi and the like, increased vascular permeability, migration and activation of neutrophils, monocytes, macrophages, eosinophils and the like are known. It has also been reported that PAF is involved in lowering blood pressure, ulceration, establishment of pregnancy and delivery, etc.
Thus, PAF mediates a wide range of actions, including asthma, adult respiratory distress syndrome, arthritis, various diseases of the cardiovascular system, glomerulonephritis, ischemic intestinal necrosis, pancreatitis,
Ulcer, myocardial ischemia, cerebral ischemia, rejection to transplant, cold urticaria, shock due to anaphylaxis or sepsis, etc.
It is known that PAF is greatly involved in various clinically important diseases (Med. Res. Re).
v. , 10, 351-370, 1990).

[0004] Since PAF plays an important role in vivo as described above, an antagonist or blocker for the action of PAF is expected to be useful as a pharmaceutical.
On the other hand, recently, the present inventors have proposed a crude drug, white flower maize (Pe).
ucedanum Praeruptorum Duu
One of the components of n), the lacylactone compounds praelputrin A and praelputrin B, and their derivatives were found to have antagonistic activity on the PAF receptor, and this was reported (Chem. Phar).
m. Bull. , 43, 859-847, 1995).
However, the reported PAF antagonist activity of the lacylactone compound is small, and development of a drug having a stronger PAF antagonist activity for clinical use has been desired.

[0005]

SUMMARY OF THE INVENTION It is a first object of the present invention to provide a novel silalactone derivative exhibiting excellent PAF antagonist activity. A second object of the present invention is to provide a platelet aggregation inhibitor comprising a silicateone derivative as an active ingredient.

[0006]

Means for Solving the Problems As a result of earnest studies, the present inventors have evaluated the PAF antagonist activity of a newly synthesized lacylactone derivative using the inhibitory activity of PAF on the platelet aggregation effect as an index, and obtained an excellent PAF antagonist.
The present inventors have found a novel silalactone derivative having antagonist activity, and have completed the present invention. That is, the present invention is a silicactone derivative represented by the general formula (1).

Embedded image [Wherein, R ¹ is an aliphatic hydrocarbon group having 1 to 22 carbon atoms.
One of R ² and R ³ is a hydrogen atom, and the other is the following general formula (2)

Embedded image (In the formula, one of R ⁶ and R ⁷ is a hydrogen atom and the other is a methyl group.) One of R ⁴ and R ⁵ is a hydrogen atom and the other is the following general formula (3)

Embedded image (In the formula, one of R ⁸ and R ⁹ is a hydrogen atom and the other is a methyl group.) Further, the present invention is a platelet activating factor antagonist using a silicate derivative of the general formula (1), and a platelet aggregation inhibitor.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, R ¹ in the general formula (1) represents an aliphatic hydrocarbon group having 1 to 22 carbon atoms. Examples of the aliphatic hydrocarbon group having 1 to 22 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, Linear alkyl groups such as tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, isopropyl group, isobutyl group, s-butyl group, t
A branched alkyl group such as -butyl group, isopentyl group, neopentyl group, t-pentyl group, isohexyl group, vinyl group, allyl group, isopropenyl group, cis-9-tetradecenyl group, trans-3-hexadecenyl group, c
is-9-hexadecenyl group, cis-6-octadecenyl group, cis-9-octadecenyl group, trans-
9-octadecenyl group, cis-11-octadecenyl group, cis-9-eicosenyl group, cis-13-docosenyl group, cis-2, cis-4-hexadienyl group, cis-2, trans-4-hexadienyl group,
trans-2, cis-4-hexadienyl group, tr
ans-2, trans-4-hexadienyl group, ci
s-9, cis-12-octadecadienyl group, cis
-6, cis-9-octadecadienyl group, cis-
9, cis-12, cis-15-octadecatrienyl group, cis-6, cis-9, cis-12-octadecatrienyl group, cis-9, trans-11, t
ran-13-octadecatrienyl group, cis-
5, cis-8, cis-11, cis-14-eicosatetraenyl group, cis-5, cis-8, cis-
11, cis-14, cis-17-eicosapentaenyl group, cis-4, cis-7, cis-10, ci
s-13, cis-16-docosapentaenyl group, ci
s-4, cis-7, cis-10, cis-13, c
Alkenyl groups such as is-16 and cis-19-docosahexaenyl are preferred. Among these aliphatic hydrocarbon groups having 1 to 22 carbon atoms, a linear or branched alkyl group having 1 to 22 carbon atoms is more preferable from the viewpoint of easy handling of the compound, and furthermore, having 1 to 22 carbon atoms. Straight-chain alkyl groups are most preferred.

One of R ² and R ^{3 in} the general formula (1) is a hydrogen atom, and the other is a group of the general formula (2). One of R ⁶ and R ^{7 in} the general formula (2) represents a hydrogen atom, and the other represents a methyl group. One of R ⁴ and R ^{5 in} the general formula (1) is a hydrogen atom, and the other is a group of the general formula (3). One of R ⁸ and R ^{9 in} the general formula (3) represents a hydrogen atom, and the other represents a methyl group. Of these, R ² of the silactone derivative of the general formula (1) is a group of the general formula (2), R ⁴ is a group of the general formula (3), and R ⁷ and R ⁹
Are preferably methyl groups, because they are considered to be excellent in PAF antagonist activity. However, when they are used as a pharmaceutical such as a platelet aggregation inhibitor, the compounds represented by the general formula (1) There is no particular limitation.

The silactone derivative of the present invention can be synthesized, for example, by the following method. The silalactone derivative represented by the general formula (1) is obtained by acetylating 2,4-dihydroxybenzaldehyde as a starting material with acetic anhydride, and then performing cyclocondensation using N-acetylglycine to form a coumarin skeleton. Induce. This is then described by the method of Taylor et al. (Aust. J. Chem., 24, 2347).
２３2354,1971) to induce a secerin skeleton. When this is acylated with tiglic anhydride, for example, by a conventional method, a dilacyl derivative of a silactone derivative can be obtained.

The silactone derivative of the general formula (1) thus obtained can be isolated and purified by a conventionally known method such as extraction, recrystallization, chromatography and the like. Also, using selective crystallization or isomerization columns,
It is also common to separate optical isomers and stereoisomers.

[0011] The platelet aggregation inhibitor of the present invention contains the above-mentioned silalactone derivative represented by the general formula (1) as an active ingredient. The platelet aggregation inhibitor of the present invention,
By acting as a PAF antagonist, it inhibits platelet aggregation caused by PAF, as well as asthma, adult respiratory distress syndrome, arthritis, various diseases of the cardiovascular system, glomerulonephritis, ischemic intestinal necrosis, pancreatitis, ulcer, It is effective in preventing or treating various diseases in which PAF is directly or indirectly involved, such as myocardial ischemia, cerebral ischemia, rejection to transplantation, cold urticaria, shock due to anaphylaxis or sepsis.

[0012] The platelet aggregation inhibitor of the present invention is obtained by converting a silactone derivative represented by the general formula (1) into a known pharmacologically acceptable carrier, excipient, disintegrator, corrector, extender, diluent, or the like. Agents, solubilizers and the like, mixed with a pharmaceutical composition according to a known method, for example, tablets, capsules, granules,
It can be formulated into powders, powders, pills, solvents, drinks, injections, drops, suppositories and the like. Such formulations can be administered orally or parenterally.

The dosage varies depending on the administration subject, administration route, symptoms, and the like. However, when administered orally, the dose of the silactone derivative represented by the general formula (1) is usually about 0.01 to 100 mg / dose. kg body weight, preferably about 0.01 to 10 mg / kg body weight, is administered about 1 to 3 times a day. In the case of parenteral administration, for example, in the case of suppositories, about 0.05 to 20 mg / kg body weight is administered once or twice a day as a silactone derivative represented by the general formula (1). In the case of injections of oily preparations, general formula (1)
About 0.001 to 5 as a silactone derivative represented by
It is preferred to administer mg / kg body weight once or twice a day.

[0014]

The present invention will be described in more detail with reference to examples. Example 1 The compound of the present invention (±) -cis-3-methoxy-
3 ', 4'-Dithigloylsilicactone is represented by the following [1]
To [10]. [1] Synthesis of 2,4-diacetoxybenzaldehyde 6.0 g of 2,4-dihydroxybenzaldehyde (4
3.5 mmol) in 200 ml of dehydrated ether,
40.2 g (291.5 mmol) of anhydrous potassium carbonate
And 20 ml of acetic anhydride obtained by distilling a commercially available product was added thereto, and the mixture was refluxed for 3 hours. The precipitated inorganic substance was collected by filtration, and the filtrate was distilled off under reduced pressure. Ice water and ethyl acetate were poured into the residue. After stirring for 1.5 hours, the ethyl acetate layer was separated, dried over saturated magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-hexane to give 8.8 g of colorless needle crystals of 2,4-diacetoxybenzaldehyde (yield 91.2).
%). The analysis results of this compound are as follows.

Melting point: 62-64.5 ° C. IR (cm^-1, KBr): 1767, 1690, 160
7,1586,1493 ¹H-NMR (δ (ppm),
CDCl_Three): 2.32 (3H, s, -Me), 2.3
9 (3H, s, -Me), 7.05 (1H, d, J =
2.2 Hz, aromatic H), 7.17 (1
H, dd, J = 8.4, 2.2 Hz, aromatic
 H), 7.91 (1H, d, J = 8.4 Hz, aro
magnetic H), 10.10 (1H, s, -CHO) high-resolution mass spectrometry: theoretical 222.0528 (C₁₁H_Ten
O_Five), Measured 222.0533

[2] Synthesis of 3-acetamido-7-acetoxycoumarin 3.84 g of 2,4-diacetoxybenzaldehyde (1
7.3 mmol) was dissolved in 35 ml of acetic anhydride, and 10.12 g (86.5 mmol) of N-acetylglycine and 5.67 g (69.2 mmol) of anhydrous sodium acetate were dissolved.
Was added and stirred at 90 ° C. for 11 hours. The reaction solution was poured into a mixture of ice water and chloroform, stirred for 3 hours, neutralized sequentially with 130 ml of a 30% aqueous potassium hydroxide solution and 200 ml of a saturated aqueous sodium hydrogen carbonate solution, and the chloroform layer was separated. The chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was washed with 50 ml of ether (repeated three times). Washed with 10 ml. The crystalline portion was filtered off and recrystallized from ethyl acetate-chloroform to give 3
1.44 g (yield 32.0%) of colorless needle crystals of -acetamide-7-acetoxycoumarin were obtained. The analysis results of this compound are as follows.

Melting point: 238 to 241 ° C. IR (cm ⁻¹ , KBr): 1761, 1721, 168
4,1625,1615,1539 ¹ H-NMR (δ (ppm), CDCl ₃ ): 2.24
(3H, s, -M), 2.33 (3H, s, -M)
e), 7.07 (1H, d, J = 8.0, 2.2Hz,
aromatic H), 8.04 (1H, broad)
s, -NH-), 8.67 (1H, s, olefin)
ic H) High resolution mass spectrometry: theoretical 261.0635 (C ₁₃ H ₁₀
NO ₅ ), found 261.0620

[3] Synthesis of 3-acetamido-7-hydroxycoumarin 1.0 g of 3-acetamido-7-acetoxycoumarin
(3.83 mmol) in 40 ml of methanol,
Add 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and add
For 2 hours. Ice water was added to the reaction mixture, and the mixture was acidified with a 10% aqueous hydrochloric acid solution.
And then recrystallized from methanol to give 3-acetamide-
0.82 g (yield 97.6%) of colorless needle crystals of 7-hydroxycoumarin was obtained. The analysis results of this compound are as follows.

Melting point: 309.8-311.5 ° C. IR (cm ⁻¹ , KBr): 3324, 1703, 165
7,1543 ¹ H-NMR (δ (ppm), DMSO): 2.13
(3H, s, -Me), 6.73 (1H, d, J = 2.
2 Hz, aromatic H), 6.78 (1 H, d
d, J = 8.4, 2.2 Hz, aromatic
H), 7.51 (1H, d, J = 8.4 Hz, arom
atic H), 8.49 (1H, s, olefini)
c H), 9.55 (1H, broad s, -NH
−), 10.35 (1H, broads, —OH) High-resolution mass spectrometry: theoretical value of 219.0530 (C ₁₁ H ₉
NO ₄ ), found 219.0515

[4] 3-acetamido-7- (1 ′,
Synthesis of 1'-dimethylpropynyloxy) coumarin 500 mg of 3-acetamido-7-hydroxycoumarin
(2.28 mmol) was dissolved in 60 ml of dry acetone, and 419.5 mg (3.04 mm) of anhydrous potassium carbonate was dissolved.
ol) and refluxed for 24 hours. Further, 232.6 mg of 3-chloro-3-methyl-1-butyne (2.28 m
mol), and after refluxing for 6 days, the solvent was distilled off. 40 ml of water was added to the residue, which was then made acidic with a 10% aqueous hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a 3N aqueous solution of sodium hydroxide, a saturated aqueous solution of sodium chloride and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with 2 ml of ether (2
The mixture was washed with 5 ml of methanol, and the crystalline portion was filtered off and recrystallized from ether to give 3-acetamido-7- (1 ′, 1′-dimethylpropynyloxy).
460.0 mg of colorless needle crystals of coumarin (71.0 yield)
%). The analysis results of this compound are as follows.

Melting point: 161-164 ° C. IR (cm ⁻¹ , KBr): 3233,2105,170
7, 1680, 1613, 1534 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.70
(6H, s, -M), 2.23 (3H, s, -M)
e), 2.65 (1H, s, acetylenic)
H), 7.10 (1H, dd, J = 8.6, 2.2H)
z, aromatic H), 7.30 (1H, d, J
= 2.2 Hz, aromatic H), 7.40 (1
H, d, J = 8.6 Hz, aromatic H),
7.99 (1H, broads, -NH-), 8.6
4 (1H, s, olefinic H) High resolution mass spectrometry: theoretical value 285.1002 (C ₁₆ H ₁₅
NO ₄ ), found 285.1001

[5] Synthesis of 3-acetamidoseserin 3-acetamido-7- (1 ', 1'-dimethylpropynyloxy) coumarin 380.0 mg (1.33 mmol)
l) was dissolved in 10 ml of distilled N, N-dimethylaniline and refluxed for 30 minutes. 50 ml of ice water was added to the reaction solution,
The mixture was acidified with a 10% aqueous hydrochloric acid solution and extracted with chloroform. The chloroform layer was washed with a 10% aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with ether and recrystallized from ethyl acetate to give colorless needle crystals of 3-acetamidoseserin.
8.6 mg (83.8% yield) was obtained. The analysis results of this compound are as follows.

Melting point: 214 to 219 ° C. IR (cm ⁻¹ , KBr): 1720, 1675, 164
4,1625,1600,1525 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.47
(6H, s, -M), 2.23 (3H, s, -M)
e), 5.73 (1H, d, J = 9.9 Hz, olef)
inic H), 6.75 (1H, d, J = 8.1H)
z, aromatic H), 6.85 (1H, d, J
= 9.9 Hz, olefinic H), 7.24 (1
H, d, J = 8.1 Hz, aromatic H),
7.97 (1H, broads, -NH-), 8.6
0 (1H, s, olefinic H) High-resolution mass spectrometry: theoretical value 285.1002 (C ₁₆ H ₁₅
NO ₄ ), found 285.1525

[6] Synthesis of 3-aminoseserin 1.12 g of 3-acetamidoseserin (3.93 mmol)
l) was dissolved in 20 ml of methanol, and a 3N aqueous hydrochloric acid solution 1 was added.
After 0 ml was added and the mixture was refluxed for 6.5 hours, ice water 1 was added to the reaction mixture.
0 ml was added and extracted with chloroform. The chloroform layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (developing solvent; ethyl acetate: hexane = 1: 2), and the eluted crystalline portion was recrystallized from an ether-hexane mixed solution to give 3-aminoseserin as a pale yellow plate crystal (838.2 mg). (Yield 8
7.4%). The analysis results of this compound are as follows.

Melting point: 139 to 141 ° C. IR (cm ⁻¹ , KBr): 1687, 1634, 157
^{8 1 H-NMR (δ (} ppm), CDCl 3): 1.45
(6H, s, -Me), 4.04 (1H, broad)
_{s, -NH 2), 5.71 (} 1H, d, J = 10.1H
z, olefinic H), 6.67 (1H, s, o)
lefinic H), 6.69 (1H, d, J = 8.
0 Hz, aromatic H), 6.88 (1H,
d, J = 10.1 Hz, olefinic H), 7.
03 (1H, d, J = 8.0 Hz, aromatic
H) High resolution mass analysis: Calculated 243.0893 (C ₁₄ H ₁₃
NO ₃ ), found 243.0867

[7a] Synthesis of 3-hydroxyseserin (method a) 21.9 mg of 3-aminoseserin (0.077 mmol)
l) was dissolved in 0.5 ml of methanol, 2 ml of a 3N aqueous hydrochloric acid solution was added, and the mixture was refluxed for 21 hours. 3 ml of ice water in the reaction solution
And extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to column chromatography (developing solvent; 3% methanol-chloroform mixture)
The eluted crystalline portion was recrystallized with a mixed solution of ethyl acetate-hexane to obtain 16.3 mg (yield: 74.1%) of 3-hydroxyseserin pale yellow prism-like crystals. The analysis results of this compound are as follows.

Melting point: 176 to 180 ° C. IR (cm ⁻¹ , KBr): 3382, 1697, 163
7,1599 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.46
(6H, s, -Me), 5.74 (1H, d, J = 1)
0.2 Hz, olefinic H), 6.75 (1
H, d, J = 8.5 Hz, aromatic H),
6.88 (1H, d, J = 10.2 Hz, olefin
ic H), 6.99 (1H, s, olefinic)
H), 7.14 (1H, d, J = 8.5 Hz, arom
atic H) High resolution mass analysis: Calculated 244.0706 (C ₁₄ H ₁₂
NO ₄ ), found 244.0730

[7b] Synthesis of 3-hydroxyseserin (method b) 3-Hydroxyseserin was synthesized by the following method in addition to the method described in [7a]. 750.0 mg (2.63 mmol) of 3-acetamidoseserin obtained in [5] was dissolved in 20 ml of methanol, and 60 ml of a 3N hydrochloric acid aqueous solution was added, followed by reflux for 54 hours. 50 ml of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (developing solvent; 3% methanol-chloroform mixture), and the eluted crystalline portion was recrystallized with ethyl acetate-hexane mixture to give 3-hydroxyseserin pale yellow prism-like crystals 529. 0.6 mg (82.5% yield) was obtained. The analysis results of this compound are as follows.

Melting point: 176 to 179 ° C. IR (cm ⁻¹ , KBr): 3382, 1697, 163
7,1599 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.46
(6H, s, -Me), 5.74 (1H, d, J = 1)
0.2 Hz, olefinic H), 6.75 (1
H, d, J = 8.5 Hz, aromatic H),
6.88 (1H, d, J = 10.2 Hz, olefin
ic H), 6.99 (1H, s, olefinic)
H), 7.14 (1H, d, J = 8.5 Hz, arom
atic H) High resolution mass analysis: Calculated 244.0706 (C ₁₄ H ₁₂
NO ₄ ), found 244.0733

[8] Synthesis of 3-methoxyseserin 200.0 mg of 3-hydroxyseserin (0.82 mm
ol) was dissolved in 10 ml of dehydrated acetone, and 452.6 mg (3.28 mmol) of anhydrous potassium carbonate was added thereto to give 1
After refluxing for 0 minutes, methyl iodide 1164.4 mg
(8.20 mmol) was added and refluxed for 30 minutes. After the reaction, the solvent was distilled off, and 30 ml of water was added to the residue.
The mixture was acidified with a 0% aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (developing solvent; ethyl acetate: hexane =
1: 2), and the eluted crystalline portion was recrystallized from ether to give pale yellow plate-like crystals of 3-methoxyseserin.
8 mg (70.1% yield) was obtained. The analysis results of this compound are as follows.

Melting point: 161-163 ° C. IR (cm ⁻¹ , KBr): 1732, 1628, 160
5,1572 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.46
(6H, s, -Me), 3.88 (3H, s, -OM)
e), 5.72 (1H, d, J = 10.1 Hz, ole)
finic H), 6.73 (1H, d, J = 8.4H)
z, aromaticH), 6.86 (1H, d, J =
10.1 Hz, olefinic H) High resolution mass spectrometry: theoretical value 258.0890 (C ₁₅ H ₁₄
O ₄ ), found 258.0870

[9] Synthesis of 3-methoxysilicelactone 122.2 mg (0.47 mmol) of 3-methoxyseserin
1) was dissolved in anhydrous dioxane (2 ml), and osmium tetroxide (143.3 mg, 0.58 mmol) was added. The reaction product is dehydrated dioxane 2
After adding ml, the hydrogen sulfide gas was saturated, and the deposited precipitate was filtered through celite. The filtrate was evaporated under reduced pressure, the residue was subjected to column chromatography (developing solvent; 3% methanol-chloroform mixture), and the eluted crystalline portion was recrystallized from ethyl acetate-hexane mixture to give 3-methoxysilica. 76.8 mg of colorless needle-like crystals of lactone (yield 5
5.6%). The analysis results of this compound are as follows.

Melting point: 204-206 ° C. IR (cm ⁻¹ , KBr): 3420, 1732, 163
0, 1609, 1580, 1490 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.40
(3H, s, -M), 1.44 (3H, s, -M)
e), 3.24 (1H, d, J = 6.2 Hz, -O
H), 3.85 (1H, dd, J = 4.6, 6.2H)
z, methine H), 3.90 (3H, s, -O
Me), 4.06 (1H, d, J = 4.2 Hz, -O
H), 5.20 (1H, dd, J = 4.6, 4.2H)
z, methine H), 6.79 (1H, d, J =
8.6 Hz, aromatic H), 6.84 (1
H, s, olefinic H), 7.26 (1H,
d, J = 8.6 Hz, aromatic H) High resolution mass spectrometry: theoretical 292.0945 (C ₁₅ H ₁₆
O ₆ ), found 292.0940

[10] (±) -cis-3-methoxy-
Synthesis of 3 ′, 4′-dithigroylsilactone 3-methoxysilactone 71.2 mg (0.24 mm
ol) and 349.4 mg (1.92 m) of tiglic anhydride
mol) was dissolved in 2 ml of anhydrous pyridine, and 29.3 mg (0.24 mmol) of dimethylaminopyridine was further dissolved.
Was added and stirred at 100 ° C. for 11 hours. Ice water (40 ml) was added to the reaction solution, and the mixture was stirred for 2 hours and extracted with ethyl acetate. The ethyl acetate layer was washed with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (developing solvent; ethyl acetate: hexane = 1: 1), and the eluted crystalline portion was recrystallized from ether-hexane.
81.4 mg of colorless needle-like crystals of (±) -cis-3-methoxy-3 ′, 4′-ditigloylsilicactone (yield 7)
3.2%). The analysis results of this compound are as follows.

Melting point: 81 to 86 ° C. IR (cm ⁻¹ , KBr): 1732, 1651, 163
4,1612, 1584, 1495 ¹ H-NMR (δ (ppm), CDCl ₃ ): 1.41
(3H, s, -M), 1.47 (3H, s, -M)
e), 1.75 (6H, d, J = 7.0 Hz, -M
e), 1.79 (6H, s, -Me), 3.85 (3
H, s, -OMe), 5.40 (1H, d, J = 4.9).
Hz, methyl H), 6.65 (1H, d, J)
= 4.9 Hz, methine H), 6.76 (1
H, s, olefinic H), 6.81 (1H, d,
J = 8.6 Hz, aromatic H), 7.29
(1H, d, J = 8.6 Hz, aromatic H) High-resolution mass spectrometry: theoretical value 456.1784 (C ₂₅ H ₂₈
O ₈ ), found 456.1807

From the above results, it was confirmed that (±) -cis-3-methoxy-3 ′, 4′-ditigloylsilicactone represented by the following formula (4) was obtained.

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Example 2 Platelet Aggregation Inhibition Test of (±) -cis-3-Methoxy-3 ′, 4′-Ditigloylsilicactone 50% against platelet aggregation-induced substance-induced platelet aggregation
In order to evaluate the inhibitory effect of (±) -cis-3-methoxy-3 ′, 4′-ditigloylsilicactone on the platelet aggregation substance, a platelet aggregation inhibition test was performed using the inhibitory effect (IC ₅₀ ) as an index. The procedure was as follows. 4 months old J.P. under sodium pentobarbital anesthesia W. The common carotid artery of a male rabbit was cannulated. 9 volumes of blood collected from the cannula were mixed with 1 volume of 3.8 w / v% sodium citrate, and centrifuged at 4 ° C. at 1000 rpm for 10 minutes to collect platelet-rich plasma (PRP). Next, the lower layer was centrifuged at 3000 rpm for 15 minutes to collect the upper layer of platelet poor plasma (hereinafter referred to as PPP). Platelet of PRP and PPP fractions was measured using a multi-item automatic blood cell counter (E-2000,
After the measurement using Toa Medical Electronics Co., Ltd.), the PPP fraction was added to the PRP fraction to obtain a platelet count of about 30 × 104 ce.
It was adjusted to 11 ls / μl. Put this in a special cuvette.
178 ml were taken and preincubated for 2 minutes.
In addition, (±) -cis-3-methoxy-3 ′, 4′-ditigloylsilicactone was used as a platelet aggregation inhibitor.
0.022 ml of a% DMSO solution was added. One minute later, 0.022 ml of a platelet aggregation-inducing substance was added, and the platelet aggregation rate was measured using a platelet aggregation measurement device (NBS Hema Tracer 601 manufactured by Nikko Biosciences).

In this test, the platelet aggregation was measured by changing the concentration of the (±) -cis-3-methoxy-3 ′, 4′-ditigloylsilicactone solution, and the platelet aggregation was measured. Suppress (IC ₅₀ ) (±) -cis-3-
The concentration of methoxy-3 ', 4'-ditigloylsilicactone was determined.

The above-mentioned platelet aggregation-inducing substances include PAF,
Four kinds of sodium arachidonic acid, adenosine 5'-diphosphate, and collagen were used. Each reagent was used under the following conditions. PAF: 0.01% dissolved in 0.2% bovine serum albumin
A solution having a concentration of μg / ml was used. Sodium arachidonic acid; 32.6 μg / m 2 dissolved in a 1: 1 mixture of 6 mM Na ₂ CO ₃ dissolved in 100% ethanol and 2.5 mM Tris buffer
1 was used. Adenosine 5'-diphosphate; used was dissolved in physiological saline to a concentration of 4.3 µg / ml. Collagen: used was dissolved in SKF buffer to a concentration of 30 μg / ml. The IC ₅₀ for each platelet aggregation-inducing substance was determined. The results are shown in Table 1.

[0040]

[Table 1]

From Table 1, it can be seen that I with respect to the platelet aggregation-inducing substance
As a result of confirming C ₅₀ , (±) -cis-3-methoxy-
It was confirmed that 3 ′, 4′-ditigloylsilicactone can suppress platelet aggregation and is effective as a platelet aggregation inhibitor. In particular, since it specifically inhibited platelet aggregation by PAF, (±) -cis-3-methoxy-3 ′, 4 ′
-It was confirmed that dithigloylsilicactone acts as a PAF antagonist and is effective as a platelet aggregation inhibitor for platelet aggregation derived from PAF.

Comparative Example The (±) -cis-3-methoxy-3 ′, 4 ′ of Example 2
-Instead of dithigroyl silicactone, the following formula (5)
Was evaluated in the same manner as in Example 2 using praelputrin A represented by the following formula and praelputrin B represented by the following formula (6), using the IC ₅₀ as an index. The results are shown in Table 1.

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From Table 1, the IC ₅₀ of praelputrin A and praelputrin B for PAF was calculated as (±) -c
As a result of comparison with IC _{50 of} is-3-methoxy-3 ′, 4′-ditigloylsilicactone, (±) -cis-3-
P of methoxy-3 ', 4'-ditigloylsilicactone
The potency as an AF antagonist was 5.6 times that of the natural silactone compound praelputrin A and 3.1 times that of praelputrin B. The silactone derivative of the present invention has a PA
It was confirmed to be excellent as an F antagonist or a platelet aggregation inhibitor.

[0044]

Industrial Applicability The silactone derivative of the present invention is a platelet activating factor (PAF) antagonist, has an effect of inhibiting platelet aggregation caused by a platelet aggregation-inducing substance, and has an adult respiratory distress including asthma. Syndrome, arthritis, various diseases of the cardiovascular system, glomerulonephritis, ischemic intestinal necrosis, pancreatitis, ulcer, myocardial ischemia, cerebral ischemia, rejection to transplantation, cold urticaria, anaphylaxis and shock due to sepsis, Various diseases in which PAF is directly or indirectly involved can be prevented or treated.

Claims (3)

[Claims] 1. A silactone derivative represented by the following general formula (1). Embedded image [Wherein, R ¹ is an aliphatic hydrocarbon group having 1 to 22 carbon atoms.
One of R ² and R ³ is a hydrogen atom and the other is a compound represented by the following general formula (2): (In the formula, one of R ⁶ and R ⁷ is a hydrogen atom and the other is a methyl group.) One of R ⁴ and R ⁵ is a hydrogen atom and the other is a compound represented by the following general formula (3): (In the formula, one of R ⁸ and R ⁹ is a hydrogen atom and the other is a methyl group.) ] 2. A platelet activating factor antagonist comprising the silicate derivative of claim 1 as an active ingredient. (3) A platelet aggregation inhibitor comprising the silicate derivative according to (1) as an active ingredient.